CREB (the cAMP response element-binding protein) is a key transcription factor which mediates cellular responses to a variety of extracellular stimuli. CREB has been implicated in cell survival, differentiation, and neuronal plasticity, processes fundamental to human health. While much is now known regarding the mechanisms of CREB activation, little is known about cellular mechanisms of CREB repression. Preliminary data now show that in quiescent cells CREB is associated with histone deacetylase (HDAC) activity, a known mode of transcriptional repression. This activity is released from CREB upon cell stimulation. In these studies, this HDAC activity will be characterized, investigating both the identity of the HDAC and its mechanism of recruitment. The effects of distinct stimuli on HDAC association will also be examined along with the characterization of the mechanisms that trigger HDAC release. Finally, HDAC-resistant CREB mutants will be isolated and their effects evaluated on CREB-dependent transcription and other CREB-dependent processes. This work will shed the first light on the cellular mechanisms of CREB repression and provide valuable new tools to probe the role of CREB in human health and disease.